SUMMARY Surveillance trials suggest that the risk for life-threatening asthma exacerbations and asthma-related deaths are increased with long-acting ?2-adrenergic receptor (?2AR) agonist (LABA) therapy, although prospective randomized trials, including FDA-mandated safety studies, have not confirmed these observations when LABA is combined with an inhaled corticosteroid (ICS). Despite this, the risk for adverse outcomes and treatment failure during LABA therapy is higher in African Americans compared to Whites. We have shown that rare genetic variants in the ?2-adrenergic receptor gene (ADRB2) are associated with exacerbations in asthma subjects taking LABAs. We have also shown that African ancestry is strongly associated with lower lung function in African Americans with severe asthma and COPD. These data provide a strong rationale for using conventional and functional genetic approaches to elucidate role of ancestry-specific genetic variation, including novel variants and variation in important components of the ?2AR signaling pathway, that determine beta agonist response and lung function. We hypothesize that ethnic-specific genetic variants, particularly rare variants and ?2AR pathway variation, have important effects on beta agonist response and baseline lung function. We propose the following Specific Aims: Aim 1: To identify novel genetic variants associated with beta agonist response and measures of lung function in multi-ethnic asthma and COPD cohorts using a combination of rare variant-based, admixture-based whole-genome analyses, and GWAS. We will leverage existing comprehensive genotyping with imputation and Next- Generation Sequencing (NGS) datasets from 1,919 asthma subjects from SARP1-3, 839 subjects from Asthma Clinical Research Network trials, 2,807 (1,122 African/African American and 554 Hispanic) asthma subjects from three LABA-ICS clinical trials, and 2,507 SPIROMICS subjects for the discovery of novel gene pathways associated with beta agonist response and lung function. Aim 2: To validate the effects of variants in the ?2-adrenergic receptor (?2AR) pathway and novel gene pathways on beta agonist response and lung function in multi-ethnic beta agonist-treated clinical trial cohorts. We will perform de novo NGS on 40 ?2AR pathway genes and utilize existing whole-genome sequencing data for ?2AR pathway analyses to identify novel gene-gene interactions constituting predictive genetic profiles for beta agonist response and lung function across ethnic groups .Aim 3: To validate the biologic effects of rare variants within the ?2AR signaling pathway in order to refine and support genetic predictive profiles of beta agonist therapeutic responsiveness. ?2AR pathway rare variation will be evaluated with molecular phenotyping to refine predictive genetic profiles. The proposed studies have the potential to define an at-risk subgroup of asthma susceptible to adverse effects of LABA therapy while identifying novel loci for beta agonist response or disease severity and elucidating novel mechanisms for inter-ethnic differences.